Program Project Hormonal Control of Calcium Metabolism brings together a group of highly productive investigators who have worked closely together for a number of years supported by the project and other funded research grants. Tools of chemical molecular and cellular biology plus available carefully designed genetically modified animals are used to evaluate the role of parathyroid hormone in bone and renal cell biology. Several exciting medical translational applications have already come from this work and the potential for several more is evident. Project I (Gardella PI) Mechanisms of ligand binding and activation at the PTHR1 expands on earlier work that probes molecular details of ligand/receptor activation including newly available small molecule peptidomimetics as well as new chemical strategies to alter the pharmacokinetic and therefore ultimately pharmacodynamic of PTH analogs. Important translational implications from this work have been the discovery of a long-acting form of PTH for treatment of hypoparathyroidism soon to be entering phase 1 clinical trials and development of peptide negative agonists that show promise in animal models of controlling the multiple skeletal abnormalities seen in the hereditary disorder Jansen's disease. Project II (Kronenberg PI) PTH actions on cells of the osteoblast lineage builds on earlier progress with discovery of the first specific cellular target of PTH action the SIK kinases. This discovery opens a new field of important basic science investigation into the mode of action of PTH and has important translational implications in that the small molecule kinase inhibitors already discovered might ultimately lead to an orally active agent useful in the treatment of osteoporosis. Meantime these investigators continue to probe the effects of PTH on cellular targets of PTH action in bone from earliest precursors to mature osteoblasts and osteocytes. This work in addition to its fundamental interest could help with understanding how to improve PTH action since it is known that its effect wanes after continuous use for 12 months or less even though there are bone deficits remaining. Project III (Jueppner PI) renal regulation of phosphate homeostasis and its effects on bone deals with several recent novel findings. The first is importance of signal selectivity in PTH analogs in phosphate metabolism and bone cell maturation and secondly, the implications of high bone mass seen with skeletal transgenic expression of the Jansen's disease (JMC transgene) also studying a newly available specific inhibitor of NPT2A that may prove to be useful in hereditary disorders of hyperphosphatemia and CKD. Project IV (Mannstadt and Wein co-PI?s) The role of salt inducible kinases in renal PTH action builds on the recent discovery of the importance of the SIK kinase family in PTH bone action the investigators having demonstrated convincingly in preliminary work that SIK kinases are also critical to PTH actions on the kidney.